Abstract
Trastuzumab (TZM) is a humanized monoclonal antibody that has been approved for the clinical management of HER2-positive metastatic breast and gastric cancers but its use is limited by its cumulative dose and off-target cardiotoxicity. Unfortunately, till date, there is no approved antidote to this off-target toxicity. Therefore, an acute study was designed at investigating the protective potential and mechanism(s) of CVE and IGE in TZM-induced cardiotoxicity utilizing cardiac enzyme and oxidative stress markers and histopathological endpoints. 400 mg/kg/day CVE and IGE dissolved in 5% DMSO in sterile water were investigated in Wistar rats injected with 2.25 mg/kg/day/i.p. route of TZM for 7 days, using serum cTnI and LDH, complete lipid profile, cardiac tissue oxidative stress markers assays, and histopathological examination of TZM-intoxicated heart tissue. Results showed that 400 mg/kg/day CVE and IGE profoundly attenuated increases in the serum cTnI and LDH levels but caused no significant alterations in the serum lipids and weight gain pattern in the treated rats. CVE and IGE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving TZM-associated cardiac histological lesions. These results suggest that CVE and IGE could be mediating its cardioprotection via antioxidant, free radical scavenging, and antithrombotic mechanisms, thus, highlighting the therapeutic potentials of CVE and IGE in the management of TZM-mediated cardiotoxicity.
Highlights
Trastuzumab, a humanized monoclonal antibody targeted against epidermal growth factor receptor 2 (HER2), was approved by the United States Food and Drug Administration (FDA) for the clinical management of HER2-positive breast cancers either as an adjuvant or neoadjuvant, and metastatic breast and gastric carcinomas and metastatic
In mediating its cytotoxic action, trastuzumab is known to bind to the domain IV of the extracellular domain of HER2 and triggers cascade tumorsuppressive actions including the activation of antibodydependent cell-mediated cytotoxicity, inhibition of HER2 extracellular domain cleavage, disruption of HER2 receptor homo- and heterodimerization extracellular segment of HER2 and resulting in the inhibition of HER2-mediated malignant transformation [1, 2]
Wide-scale clinical use of trastuzumabbased therapies has been significantly limited by its adverse cardiac dysfunctions and dilated cardiomyopathy-related congestive heart failures, which have been reported to occur in up to 27% of HER2-positive metastatic breast cancer patients on its combination therapy with doxorubicin [2]
Summary
Trastuzumab, a humanized monoclonal antibody targeted against epidermal growth factor receptor 2 (HER2), was approved by the United States Food and Drug Administration (FDA) for the clinical management of HER2-positive breast cancers either as an adjuvant or neoadjuvant, and metastatic breast and gastric carcinomas and metastaticOxidative Medicine and Cellular Longevity gastric cancer [1]. Trastuzumab, a humanized monoclonal antibody targeted against epidermal growth factor receptor 2 (HER2), was approved by the United States Food and Drug Administration (FDA) for the clinical management of HER2-positive breast cancers either as an adjuvant or neoadjuvant, and metastatic breast and gastric carcinomas and metastatic. Wide-scale clinical use of trastuzumabbased therapies has been significantly limited by its adverse cardiac dysfunctions and dilated cardiomyopathy-related congestive heart failures, which have been reported to occur in up to 27% of HER2-positive metastatic breast cancer patients on its combination therapy with doxorubicin [2]. As a clinical strategy of preventing the development of trastuzumabinduced cardiotoxicity, Wu et al [8] recently investigated and reported the clinical efficacy and attenuation of trastuzumab-induced cardiac dysfunction in HER2positive breast cancer patients using fixed 440 mg dose monthly administration of trastuzumab. Till date, there are no approved effective therapeutic agent(s) available that could prevent the development of this unwanted/adverse effect of trastuzumab without comprising its efficacy
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